Cell-of-origin targeted drug repurposing for triple-negative and inflammatory breast carcinoma with hdac and hsp90 inhibitors combined with niclosamide

Abstract

Accurate methods for detecting cancer and for determining the prognosis of cancer, including breast cancer, are described herein, using biomarkers referred to herein as the ET-29, HDAC1, HDAC7, and ZNF92. Upregulation of HDAC1, HDAC7, and ZNF92 and optionally one or more genes in ET-29 biomarkers predicts sensitivity to a three-drug combination that includes histone deacetylase inhibitor(s) (HDAC), heat shock protein 90 (HSP90) inhibitor(s), and helminth(s).

We claim: 
     
         1 . A method comprising:
 a. assaying a biological sample from a subject for expression of HDAC1, HDAC7, and ZNF92 genes to determine one or more expression levels for the HDAC1, HDAC7, and ZNF92 genes;   b. comparing the determined expression levels with one or more reference values to identify any altered expression levels in the subject's biological sample, wherein altered expression levels of the HDAC1, HDAC7, and ZNF92 genes in the biological sample relative to the reference value indicates that the subject has cancer with poor prognosis or the subject has malignant cancer, and absence of altered expression of the HDAC1, HDAC7, and ZNF92 genes relative to the reference value indicates that the subject does not have a cancer with poor prognosis or does not have malignant cancer; and optionally   c. administering one or more histone deacetylase inhibitor(s) (HDAC), one or more inhibitor of heat shock protein 90 (HSP90), and one or more helminths to a subject determined to have a cancer with poor prognosis or a malignant cancer.   
     
     
         2 . The method of  claim 1 , wherein the biological sample from the subject is further assayed for expression of one or more genes encoding an amino acid sequence having at least 90% sequence identity to any of SEQ ID NOs: 3-31. 
     
     
         3 . The method of  claim 1 , wherein the sample is a breast cancer sample. 
     
     
         4 . The method of  claim 1 , wherein the sample is a cervical cancer sample, uterine cancer, or prostate cancer. 
     
     
         5 . The method of  claim 1 , further administering one or more of ML239, Tipifarnib, Tivantinib, CHIR-99021, Tubastatin-A, GDC-0879, SB-525334, PRIMA-1-met, or a combination thereof, to the subject. 
     
     
         6 . The method of  claim 1 , wherein the administering one or more histone deacetylase inhibitor(s), one or more heat shock factor inhibitor, and the one or more helminths are delivered simultaneously. 
     
     
         7 . The method of  claim 1 , wherein the sample is a physiological fluid sample, a tumor tissue sample, or a cancer cell sample. 
     
     
         8 . The method of  claim 1 , wherein the subject is a human. 
     
     
         9 . The method of  claim 8 , wherein the mammal has inflammatory breast cancer. 
     
     
         10 . The method of  claim 8 , wherein the mammal has triple negative breast cancer. 
     
     
         11 . The method of  claim 1 , wherein RNA expression is assayed. 
     
     
         12 . The method of  claim 1 , wherein protein expression is assayed. 
     
     
         13 . The method of  claim 1 , wherein the inhibitor of HSP90 comprises an inhibitor of HSP90a and HSP900. 
     
     
         14 . The method of  claim 1 , wherein the inhibitor of HSP90 comprises an antibiotic. 
     
     
         15 . The method of  claim 1 , wherein the inhibitor of HSP90 is Pimitespib, Tanespimycin, or a combination thereof. 
     
     
         16 . The method of  claim 1 , wherein the helminth is niclosamide. 
     
     
         17 . The method of  claim 1 , wherein the at least one HDAC inhibitor is Belinostat, Entinostat, Vorinostat, or a combination thereof. 
     
     
         18 . A method to prevent, inhibit or treat cancer in a mammal, comprising: administering to the mammal a composition comprising one or more histone deacetylase inhibitor(s), one or more heat shock factor inhibitor, and one or more helminths, wherein the cancer in the mammal is determined to have altered expression levels of HDAC1, HDAC7, and ZNF92 genes, relative to a reference value. 
     
     
         19 . The method of  claim 18 , wherein the cancer in the mammal is determined to have altered expression levels of a protein having an amino acid sequence having at least 90% sequence identity to any of SEQ ID NOs: 3-31. 
     
     
         20 . The method of  claim 18 , wherein the mammal is a human. 
     
     
         21 . The method of  claim 18 , wherein the mammal has breast cancer, cervical cancer, uterine cancer, or prostate cancer. 
     
     
         22 . A method comprising: (a) contacting cancer cells expressing HDAC1, HDAC7, or ZNF92 genes or producing HDAC1, HDAC7, or ZNF92 proteins with a test agent; (b) measuring HDAC1, HDAC7, or ZNF92 RNA or protein expression levels in the cells or measuring HDAC1, HDAC7, or ZNF92 protein activity levels; and (c) determining that the test agent reduces the expression levels or activity levels of HDAC1, HDAC7, or ZNF92 genes, to thereby identifying a test agent as a candidate agent that reduces HDAC1, HDAC7, or ZNF92 genes expression levels or activity levels. 
     
     
         23 . A pharmaceutical composition comprising one or more histone deacetylase inhibitor(s), one or more heat shock factor inhibitor, and one or more helminths.